Transcriptional repression of Transforming Growth Factor-P type 11 receptor (T beta RII) gene has been proposed to be one of the major mechanisms leading to TGF-beta resistance. In this study, we demonstrate that expression of Caveolin-1 (Cav-1) gene in NIH3T3 fibroblast cells down-regulates the expression of T beta RII gene in the transcriptional level, eventually resulting in the decreased responses to TGF-beta. The reduced expression of T beta RII gene by Cav-1 appeared to be due to the changes of the sequence-specific DNA binding proteins to either Positive Regulatory Element I (PRE1) or PRE2 of the T beta RII promoter. In addition, Cav-1 expression inhibited TGF-beta-mediated cellular proliferation and Plasminogen Activator Inhibitor (PAI)-1 gene expression as well as TGF-beta-induced luciferase activity. Furthermore, the inhibition of endogeneous Cav-1 by small interfering RNA increased the expression of T beta RII gene. These findings strongly suggest that expression of Cav-1 leads to the decreased cellular responsiveness to TGF-beta through down-regulating T beta RII gene expression. (c) 2007 Elsevier Inc. All rights reserved.